AbstractNLRs (nucleotide-binding domain leucine-rich-repeat-containing receptors; NOD-like receptors) are a class of pattern recognition receptor (PRR) that respond to host perturbation from either infectious agents or cellular stress1,2. The function of most NLR family members has not been characterized and their role in instructing adaptive immune responses remains unclear2,3. NLRP10 (also known as PYNOD, NALP10, PAN5 and NOD8) is the only NLR lacking the putative ligand-binding leucine-rich-repeat domain, and has been postulated to be a negative regulator of other NLR members, including NLRP3 (refs 4鈥?). We did not find evidence that NLRP10 functions through an inflammasome to regulate caspase-1 activity nor that it regulates other inflammasomes. Instead, Nlrp10鈭?鈭?/i> mice had a profound defect in helper T-cell-driven immune responses to a diverse array of adjuvants, including lipopolysaccharide, aluminium hydroxide and complete Freund鈥檚 adjuvant. Adaptive immunity was impaired in the absence of NLRP10 because of a dendritic cell (DC) intrinsic defect in emigration from inflamed tissues, whereas upregulation of DC costimulatory molecules and chemotaxis to CCR7-dependent and -independent ligands remained intact. The loss of antigen transport to the draining lymph nodes by a subset of migratory DCs resulted in an almost absolute loss in naive CD4+ T-cell priming, highlighting the critical link between diverse innate immune stimulation, NLRP10 activity and the immune function of mature DCs. Subscription info for Chinese customersWe have a dedicated website for our Chinese customers. Please go to naturechina.com to subscribe to this journal.Go to naturechina.comRent or Buy articleGet time limited or full article access on ReadCube.from$8.99Rent or BuyAll prices are NET prices. Data deposits The microarray data discussed in this publication have been deposited in NCBI鈥檚 Gene ExpressionOmnibus and are accessible through GEO Series accession number GSE36009. Change history25 November 2015Nature 484, 510鈥?13 (2012); 10.1038/nature11012 In this Letter, we reported that NLRP10-deficient mice had no defect in inflammasome function in macrophages or dendritic cells (DCs). Instead, a loss of T-cell-dependent immune responses was seen in these mice secondary to a defect in DC migration. Wehave since noticed a change in the phenotype of the NLRP10-knockout mice involving DC migration, after backcrossing them onto backgrounds such as FVB or BALB/c (see Supplementary Methods).References1Takeuchi, O. Akira, S. Pattern recognition receptors and inflammation. Cell 140, 805鈥?20 (2010)CAS聽 Article聽Google Scholar聽 2Williams, A., Flavell, R. A. Eisenbarth, S. C. The role of NOD-like receptors in shaping adaptive immunity. Curr. Opin. 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Medzhitov and M. Albert for discussion and review of this manuscript, and F. Duffy for assistance with manuscript preparation. S.C.E. was supported by T32HL007974, K08AI085038 and Yale CTSA (UL1 RR024139). O.R.C. was supported by the Damon Runyon Cancer Research Foundation (DRG 108-09), the Yale CTSA (UL1 RR024139 and 5KL2RR024138), the Yale SPORE in Skin Cancer (1 P50 CA121974) and the Dermatology Foundation. E.E. is supported by Cancer Research Institute, the American Physicians for Medicine in Israel Foundation, and the United States-Israel binational Foundation grant. A.M.H., D.G.G. and in vivo imaging were supported by Yale Rheumatologic Disease Research Core Center P30AR053495. F.S.S. was supported by R01AI087630 and an Edward Mallinckrodt, Jr. Foundation scholarship. A.W. was a Howard Hughes fellow and R.A.F. is an Investigator of the Howard Hughes Medical Institute.Author informationAuthor notesStephanie C. Eisenbarth and Adam Williams: These authors contributed equally to this work.AffiliationsDepartment of Laboratory Medicine, Yale University School of Medicine, New Haven, 06520, Connecticut, USAStephanie C. Eisenbarth,聽David G. Gonzalez,聽Lan Xu聽 聽Ann M. HabermanDepartment of Immunobiology, Yale University School of Medicine, New Haven, 06520, Connecticut, USAAdam Williams,聽Till Strowig,聽Anthony Rongvaux,聽Jorge Henao-Mejia,聽Christoph A. Thaiss,聽Lauren A. Zenewicz,聽Eran Elinav聽 聽Richard A. FlavellDepartment of Dermatology, Yale University School of Medicine, New Haven, 06520, Connecticut, USAOscar R. Colegio聽 聽Lan XuDepartment of Pathology, Yale University School of Medicine, New Haven, 06520, Connecticut, USAHailong Meng聽 聽Steven H. KleinsteinDepartment of Internal Medicine, Inflammation Program, University of Iowa, Iowa City, 52242, Iowa, USASophie Joly聽 聽Fayyaz S. SutterwalaInterdepartmental Program in Computational Biology and Bioinformatics, Yale University School of Medicine, New Haven, 06520, Connecticut, USASteven H. KleinsteinHoward Hughes Medical Institute, Yale University School of Medicine, New Haven, 06520, Connecticut, USARichard A. FlavellVeterans Affairs Medical Center, Iowa City, 52241, Iowa, USAFayyaz S. SutterwalaAuthorsStephanie C. EisenbarthView author publicationsYou can also search for this author in PubMed聽Google ScholarAdam WilliamsView author publicationsYou can also search for this author in PubMed聽Google ScholarOscar R. ColegioView author publicationsYou can also search for this author in PubMed聽Google ScholarHailong MengView author publicationsYou can also search for this author in PubMed聽Google ScholarTill StrowigView author publicationsYou can also search for this author in PubMed聽Google ScholarAnthony RongvauxView author publicationsYou can also search for this author in PubMed聽Google ScholarJorge Henao-MejiaView author publicationsYou can also search for this author in PubMed聽Google ScholarChristoph A. ThaissView author publicationsYou can also search for this author in PubMed聽Google ScholarSophie JolyView author publicationsYou can also search for this author in PubMed聽Google ScholarDavid G. GonzalezView author publicationsYou can also search for this author in PubMed聽Google ScholarLan XuView author publicationsYou can also search for this author in PubMed聽Google ScholarLauren A. ZenewiczView author publicationsYou can also search for this author in PubMed聽Google ScholarAnn M. HabermanView author publicationsYou can also search for this author in PubMed聽Google ScholarEran ElinavView author publicationsYou can also search for this author in PubMed聽Google ScholarSteven H. KleinsteinView author publicationsYou can also search for this author in PubMed聽Google ScholarFayyaz S. SutterwalaView author publicationsYou can also search for this author in PubMed聽Google ScholarRichard A. FlavellView author publicationsYou can also search for this author in PubMed聽Google ScholarContributionsS.C.E. and A.W. wrote the manuscript, designed, performed and interpreted experiments with technical assistance from L.X., F.S.S. generated Nlrp10鈭?鈭?/i>
mice, S.J. performed in vitro inflammasome activation, O.R.C. and J.H.-M. assisted with trans-well assays and performed real-time PCR, L.A.Z. assisted with EAE experiments, T.S. assisted with TNP immunizations, A.R. assisted with intravenous LPS experiments, E.E. provided technical assistance with DC isolations, C.A.T. performed immunofluorescence experiments, H.M. and S.H.K. performed array analysis, D.G. and A.M.H. performed intravital microscopy and quantification. R.A.F. assisted in experimental design and interpretation. S.C.E. and R.A.F. directed the project.Corresponding authorsCorrespondence to Stephanie C. Eisenbarth or Richard A. Flavell.Ethics declarations Competing interests The authors declare no competing financial interests. Supplementary information Supplementary InformationThis file contains Supplementary Figures 1-13. (PDF 1482 kb)Supplementary Movie 1This movie shows intravital imaging of WT and Nlrp10-/- dendritic cells in the skin. After an overnight stimulation with 1 渭g/ml of LPS, 0.5 x 105 WT DCs labelled with CMTMR (Red) and 0.5 x 105 Nlrp10-/- DCs cells labelled with CFSE (Green) were mixed with an equal number of unlabelled WT and Nlrp10-/- DCs and co-injected intradermally with LPS into the ears of WT mice. Intravital two-photon laser scanning microscopy was performed four hours later. A blue emission resulting from second harmonic generation of collagen fibres highlights the epidermal junction. Images of skin adjacent to the injection site were collected every 30 seconds over the course of 60 minutes. The rendered movie represents a maximum intensity projection of a stack of 15 optical sections of a 400 um field of view. Movie is representative of three independent experiments. (MOV 4592 kb)Supplementary Movie 2This movie shows intravital microscopy of WT and Nlrp10-/- dendritic cells in the skin. After an overnight stimulation with 1 渭g/ml of LPS, 1 x 105 WT DCs labelled with CMTMR (Red) and 1 x 105 Nlrp10-/- DCs cells labelled with CFSE (Green) were co-injected intradermally with LPS into the ears of WT mice and imaged as in Movie 1 four hours later. Images were collected every 30 seconds over the course of 80 minutes and the rendered movie represents a maximum intensity projection of a stack of 15 optical sections digitally zoomed to a 350 um field of view. Importantly, swapping the dye label between the WT and Nlrp10-/- DCs did not affect the results obtained by 2-photon microscopy (data not shown). (MOV 6740 kb)PowerPoint slides PowerPoint slide for Fig. 1PowerPoint slide for Fig. 2PowerPoint slide for Fig. 3PowerPoint slide for Fig. 4Rights and permissionsReprints and PermissionsAbout this articleCite this articleEisenbarth, S., Williams, A., Colegio, O. et al. NLRP10 is a NOD-like receptor essential to initiate adaptive immunity by dendritic cells. Nature 484, 510鈥?13 (2012). https://doi.org/10.1038/nature11012Download citationReceived: 13 September 2011Accepted: 02 March 2012Published: 25 April 2012Issue Date: 26 April 2012DOI: https://doi.org/10.1038/nature11012 Fillipe M. de Ara煤jo, Lorena Cuenca-Bermejo, Emiliano Fern谩ndez-Villalba, Silvia L. Costa, Victor Diogenes A. Silva Maria Trinidad Herrero Cellular and Molecular Neurobiology (2021) CommentsBy submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate. Editorial SummaryRegulation of dendritic-cell immunityNOD-like receptors are cytoplasmic proteins involved in instructing the adaptive immune response. The function of one of these molecules 鈥?the atypical NLRP10, which lacks a putative ligand-binding leucine-rich-repeat domain 鈥?has been studied in mice engineered to be deficient in it. In the absence of functional NLRP10, dendritic cells were unable to initiate T-lymphocyte priming, and mice lacking NLRP10 were unable to respond to immunization with various adjuvants. This work suggests that activating and inhibitory ligands for NLRP10 could be of use in the development of vaccines and immunosupressants. Sign up for the Nature Briefing newsletter 鈥?what matters in science, free to your inbox daily.
